Relative Bioavailability/Bioequivalence of Different Formulations of Selinexor, the Impact of Hepatic Impairment on Selinexor Pharmacokinetics, Tolerability and Antitumor Activity of Selinexor Combination Treatment

NCT04256707 | Completed Phase 1 FDA Drug

• 1 other identifier: KCP-330-027
• Study Type: interventional
• Target: 126
• Locations: 1 country
• Sites: 11

Brief Summary

This is a Phase 1/2, two-part, multi-arm, open-label study in patients with normal Hepatic Function (HF), with either Non-small cell lung cancer (NSCLC), who have had 1-2 prior lines of treatment, with 1 line containing a checkpoint Inhibitor (CPI); or patients with normal HF, with colorectal cancer (CRC) who have had 1-3 prior lines (KRAS wild-type \[WT\]) or 1-2 prior lines (mutant KRAS) of treatment with no CPI; or patients with impaired HF, with any solid tumor, who have had at least 1 prior line of treatment. The study will comprise 2 treatment periods (monotherapy and combination therapy). The purposes of this study, during Monotherapy period, are: (1) to determine the relative bioavailability of the 100 milligrams (mg) (Tablet B) and 20 mg (Tablet A) tablets of selinexor at 100 mg once weekly (QW) dose in patients with normal hepatic function; and (2) to assess the PK of selinexor after a single dose of 40 mg (2 × 20 mg), among patients with moderate and severe hepatic impairment, relative to 100 mg (5 × 20 mg), among patients with normal hepatic function; and, during the Combination therapy period, to assess the preliminary anti-tumor activity of selinexor in combination with docetaxel in patients with NSCLC and with pembrolizumab or folinic acid, 5-fluorouracil, and irinotecan (FOLFIRI) in patients with CRC.

Conditions

Non-Small Cell Lung Carcinoma (NSCLC); Colorectal Cancer (CRC); Other Solid Tumors

Keywords

Non-small cell lung carcinoma; Selinexor; Docetaxel; Colorectal cancer; KPT-330; Bioequivalence; Relative bioavailability; Pharmacokinetics; Other Solid Tumors

Outcome Measures

Primary Outcomes (5)

• Monotherapy Period: Area Under the Concentration-Time Curve from Time Zero to Time of Last Concentration (AUC 0-t) of Selinexor in Patients with Normal, Moderate and Severe Hepatic Function

  Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 30, and 48 hours post-dose on Days 1 and 8

• Monotherapy Period: Area Under the Concentration-Time Curve from Time Zero Extrapolated to Infinity (AUC 0-inf) of Selinexor in Patients with Normal, Moderate and Severe Hepatic Function

  Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 30, and 48 hours post-dose on Days 1 and 8

• Monotherapy Period: Maximum Plasma Concentration (Cmax) of Selinexor in Patients with Normal, Moderate and Severe Hepatic Function

  Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 30, and 48 hours post-dose on Days 1 and 8

• Combination Therapy Period: Arm A and B: Overall Response Rate (ORR) as Assessed by Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

  Up to 36 months

• Combination Therapy Period: Arm C: Number of Patients With Adverse Events (AEs)

  From start of study drug administration up to survival follow-up (Up to 36 months)

Secondary Outcomes (17)

• Monotherapy Period: Time to Maximum Observed Concentration (Tmax) of Selinexor in Patients with Normal, Moderate and Severe Hepatic Impairment

  Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 30, and 48 hours post-dose on Days 1 and 8

• Monotherapy Period: Terminal Elimination Rate Constant (Lambda z) of Selinexor in Patients with Normal, Moderate and Severe Hepatic Impairment

  Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 30, and 48 hours post-dose on Days 1 and 8

• Monotherapy Period: Terminal Half-Life (t1/2) of Selinexor in Patients with Normal, Moderate and Severe Hepatic Impairment

  Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 30, and 48 hours post-dose on Days 1 and 8

• Monotherapy Period: Apparent Clearance (CL/F) of Selinexor in Patients with Normal, Moderate and Severe Hepatic Impairment

  Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 30, and 48 hours post-dose on Days 1 and 8

• Monotherapy Period: Apparent Volume of Distribution (Vd/F) of Selinexor in Patients with Normal, Moderate and Severe Hepatic Impairment

  Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 30, and 48 hours post-dose on Days 1 and 8

Study Arms (5)

Monotherapy: Normal Hepatic Function (Selinexor)

EXPERIMENTAL

(Closed for Enrollment) Cohort 1: * Week 1: selinexor 5 x 20-mg tablet daily; * Week 2: selinexor 1 x 100-mg tablet daily Cohort 2: * Week 1: selinexor 1 x 100-mg tablet daily; * Week 2: selinexor 5 x 20-mg tablet daily.

Drug: Selinexor 100 mg

Monotherapy: Impaired Hepatic Function (Selinexor)

EXPERIMENTAL

Cohort 3: Patients with Moderate Hepatic Impairment with any Solid Tumors; \- Selinexor 2 x 20-mg tablet once weekly (QW). Cohort 4: Patients with Severe Hepatic Impairment with any Solid Tumors; \- Selinexor 2 x 20-mg tablet QW.

Drug: Selinexor 40 mg

Combination Therapy: NSCLC Arm A: (Selinexor + Docetaxel)

EXPERIMENTAL

(Closed for Enrollment) Selinexor 60 mg oral dose QW and docetaxel 75 mg/m\^2 intravenously (IV) once every 3 weeks (Non-small cell lung cancer \[NSCLC\] patients).

Drug: Docetaxel; Drug: Selinexor 60 mg

Combination Therapy: CRC Arm B: (Selinexor + Pembrolizumab)

EXPERIMENTAL

(Closed for Enrollment) Selinexor 80 mg oral does QW and pembrolizumab 200 mg IV every 3 weeks (Colorectal cancer \[CRC\] Patients).

Drug: Pembrolizumab; Drug: Selinexor 80 mg

Combination Therapy: CRC Arm C: (Selinexor + FOLFIRI)

EXPERIMENTAL

(Closed for Enrollment) Cohort 1: Selinexor 40 mg oral dose Days 1, 3, 15 and 18 in a 28-day cycle and FOLFIRI (irinotecan 180 mg/m\^2; leucovorin 400 mg/m\^2; 5- fluorouracil (5-FU) 400 mg/m\^2 bolus then 5-FU 2400 mg/m\^2 continuous over 46-48 hours; IV on Day 1 and 15 in a 28-day cycle) (CRC Patients). Cohort 2: Selinexor 80 mg oral dose Days 1 and 15 in a 28-day cycle and FOLFIRI (irinotecan 180 mg/m\^2; leucovorin 400 mg/m\^2; 5-FU 400 mg/m\^2 bolus then 5-FU 2400 mg/m\^2 continuous over 46-48 hours; IV on Day 1 and 15 in a 28-day cycle) (CRC Patients).

Drug: FOLFIRI; Drug: Selinexor 40 mg; Drug: Selinexor 80 mg

Interventions

Selinexor 100 mg DRUG

100-mg 2 formulations: * 5 × 20-mg tablets (Tablet A) * 1 × 100-mg tablet (Tablet B)

Also known as: Xpovio®

Monotherapy: Normal Hepatic Function (Selinexor)

Docetaxel DRUG

75 mg/m\^2 IV

Also known as: Taxotere®

Combination Therapy: NSCLC Arm A: (Selinexor + Docetaxel)

Pembrolizumab DRUG

200 mg IV

Also known as: Keytruda®

Combination Therapy: CRC Arm B: (Selinexor + Pembrolizumab)

FOLFIRI DRUG

FOLFIRI: * Irinotecan 180 mg/m\^2 * Leucovorin 400 mg/m\^2 * 5-FU 400 mg/m\^2 bolus * 5-FU 2400 mg/m\^2 IV

Combination Therapy: CRC Arm C: (Selinexor + FOLFIRI)

Selinexor 40 mg DRUG

\- 2 × 20-mg tablets (Tablet A)

Also known as: Xpovio®

Combination Therapy: CRC Arm C: (Selinexor + FOLFIRI); Monotherapy: Impaired Hepatic Function (Selinexor)

Selinexor 80 mg DRUG

\- 4 × 20-mg tablets (Tablet A)

Also known as: Xpovio®

Combination Therapy: CRC Arm B: (Selinexor + Pembrolizumab); Combination Therapy: CRC Arm C: (Selinexor + FOLFIRI)

Selinexor 60 mg DRUG

\- 3× 20-mg tablets (Tablet A)

Also known as: Xpovio®

Combination Therapy: NSCLC Arm A: (Selinexor + Docetaxel)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Are greater than or equal to \[≥\] 18 years of age at the time of informed consent.
• Have histologically confirmed solid tumor (any type of advanced or metastatic solid tumor for the Hepatic Impairment Arm of the Monotherapy Part), advanced or metastatic NSCLC or CRC and evidence of measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
• Willing to provide signed written informed consent in accordance with federal, local, and institutional guidelines and comply with all requirements of the study.
• Female patient of childbearing potential must have a negative serum pregnancy test at screening and agree to use highly effective (dual methods of) contraception throughout the study and for 4 months following the last dose of study drug; and male patients must use an effective barrier method of contraception throughout the study and for 4 months following the last dose of study drug if sexually active. Male patients must agree not to donate sperm during the study treatment period.
• For the Monotherapy Part only (bioavailability/bioequivalence \[BA/BE\] and hepatic impairment \[HI\] arms):
• Have received at least 1 line of systemic anticancer treatment unless there is no first-line standard of care therapy or standard of care therapy is contraindicated adjuvant or neoadjuvant therapy is not counted as one line of systemic therapy). Patients must have failed prior standard curative therapy for their disease, must be intolerant to or be ineligible for any potentially curative approved treatment, irrespective of line of therapy.
• Must have either normal hepatic function, or moderate or severe hepatic impairment (as defined by the NCI organ dysfunction working group (NCI-ODWG) criteria:
• S20-100 and S100-20 arms: normal hepatic function (total bilirubin and aspartate aminotransferase \[AST\] less than or equal to \[≤\] upper limit of normal \[ULN\]).
• Note: Patients with mild hepatic dysfunction (total bilirubin greater than \[\>\] 1 to 1.5 × ULN or AST \> ULN) may be included if liver function tests are stable for the past 3 months and enrollment is approved in writing by the Sponsor's Medical Monitor.
• MHI arm: ≥1 week of documented moderate hepatic impairment (total bilirubin \>1.5-3 × ULN, any level of AST).
• SHI arm: ≥1 week of documented severe hepatic impairment (total bilirubin \>3-10 × ULN, any level of AST).
• For Combination Therapy Part only:
• Previous treatment lines (adjuvant or neoadjuvant therapy is not counted as one line of systemic therapy):
• Arm A: For patients with NSCLC, have received 1-2 prior lines of systemic anti-cancer treatment with 1 regimen including an anti-PD-1/L1 monoclonal antibody (mAb)
• Arm B: For patients with RAS mutant CRC, 1-2 prior lines of systemic treatments, and no prior anti- programmed cell death protein 1/L1 monoclonal antibody (anti-PD-1/L1 mAb).

You may not qualify if:

• Have inadequate hematopoietic function defined as (without transfusion or growth factor support within 7 days prior to first dose):
• a. absolute neutrophil count (ANC) \<1.5 × 109/liter (L); platelet count (PLT) \<100 × 109/L; or hemoglobin (Hb) \<9 gram per deciliter (g/dL).
• Have inadequate renal function defined as a calculated creatinine clearance (CrCl) of \<20 mL/min using the formula of Cockcroft and Gault.
• Have any other medical condition especially any gastrointestinal (GI) dysfunctions or GI disease that could interfere with the absorption of selinexor (e.g., inability to swallow or retain oral medications, malabsorption syndrome, a history of GI surgery which may result in intestinal blind loop, significant gastroparesis, unresolved nausea, vomiting, or diarrhea \[National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade \>1\]).
• Ongoing infection requiring parenteral antibiotics, antivirals, or antifungals on Day 1 dosing.
• Prior exposure to a SINE compound or selinexor.
• Insufficient time since or not recovered from procedures or anti-cancer therapy, defined as:
• Not recovered from major surgery ≤21 days prior to Day 1 dosing. Minor procedures, such as biopsies, dental work, or placement of a port or intravenous (IV) line for infusion are permitted.
• Have ongoing clinically significant anti-cancer therapy-related toxicities CTCAE Grade \>1. Patients with any of the following will not be excluded: immune checkpoint-related endocrinopathies that are well controlled with hormonal supplements, patients with electrolyte abnormalities that are well-managed with supplementation, patients with Grade 2 lymphopenia, or patients with alopecia of any grade. In specific cases, patients whose toxicity has stabilized or with Grade 2 non-hematologic toxicities can be allowed following documented approval by the Sponsor's Medical Monitor.
• Had last dose of previous anti-cancer therapy ≤14 days prior to Day 1 dosing.
• Palliative radiotherapy \>14 days prior to the study is allowed.
• Received investigational drugs in other clinical trials within 28 days, or 5 half-lives of the investigational drug (whichever is shorter), prior to Cycle 1 Day 1 (C1D1).
• Serious active psychiatric or active medical condition that could interfere with participation in the study or in the opinion of the Investigator would make study involvement unreasonably hazardous.
• In the opinion of the Investigator, patients who are below their ideal body weight and would be unduly impacted by changes in their weight.
• Known allergy to selinexor (all patients), docetaxel (NSCLC Arm A only), pembrolizumab (CRC arm B only), OR 5-FU, leucovorin, or irinotecan (CRC Arm C only).

Sponsors & Collaborators

• Karyopharm Therapeutics Inc: lead

Study Sites (11)

Hadassah Ein Karem University Hospital

Jerusalem, Jerusalem, 91120, Israel

Location

University Hospital Assuta Ashdod

Ashdod, 7747629, Israel

Location

Soroka University Medical Center

Beersheba, 84101, Israel

Location

Oncology Department Hillel Yaffe Medical Center

Hadera, 38100, Israel

Location

Rambam Health Care Campus

Haifa, 3109601, Israel

Location

Shaarei Zedek Medical Center

Jerusalem, 9103102, Israel

Location

Meir Medical Center

Kfar Saba, 4428164, Israel

Location

Galilee Medical Center

Nahariya, 22100, Israel

Location

Rabin Medical Center

Petah Tikva, 49100, Israel

Location

Tel-Aviv Sourasky Medical Center

Tel Aviv, 64239, Israel

Location

Sheba Medical Center

Tel Litwinsky, 5265601, Israel

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms

Interventions

selinexor; Docetaxel; pembrolizumab; IFL protocol

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Two part study (monotherapy period and combination therapy period).

Study Record Dates

• First Submitted: February 3, 2020
• First Posted: February 5, 2020
• Study Start: January 14, 2020
• Primary Completion: July 31, 2024
• Study Completion: July 31, 2024
• Last Updated: March 19, 2025

Record last verified: 2025-03

Locations

IL (11)